Diffusion weighted imaging (DWI) has an established role in detecting acute brain injury, most notably in the early detection of stroke. The application of cardiac diffusion- weighted MRI (cDWI) is similarly relevant for non-invasive assessment of myocardial injury; however, in vivo cDWI remains a major technical challenge since bulk and pulsatile motion of the beating heart make resolving molecular diffusion much more problematic than it is in the brain. A promising application for cDWI is in heart transplantation for surveillance of allograft rejection. Heart transplant (HT) patients undergo routine monthly endomyocardial biopsies (EMB) in the first year and annual intra-arterial coronary angiography (ICA) to monitor for acute and chronic rejection, respectively. These tests are invasive and carry risks of valve damage, renal failure and cardiac perforation. Additionally, this surveillance practice is resource-demanding, adding to the enormous cost of HT. For over 25,000 Americans living with HT, a non-invasive method of graft surveillance - allowing for safe deferral of costly and invasive tests - is highly desirable. The goal of this project is to develop a robust cDWI technique for clinical use, with initial validation in HT patients for non-invasive surveillance of acute and chronic rejection. We propose to overcome the current limitations of cDWI using a short-axis propeller echo-planar imaging (SAP- EPI) MR sequence. By combining the ultra-fast EPI technique with a novel SAP motion-correction algorithm, the challenge of physiologic motion will be addressed while minimizing image distortion of standard EPI; additionally, this acquisition method is inherently flexible and can be reconstructed for high-resolution and time- resolved cardiac imaging. Aim 1 is sub-divided into technical (1A) and clinical (1B) goals: Aim 1A is focused on cDWI sequence development and retrospective correction of motion- induced cardiac errors and signal loss. SAP motion- correction will be developed to deal with the physiologic motion of the beating heart. Aim 1B will explore if cDWI can detect acute myocardial damage in the setting of acute cellular rejection (ACR) in HT patients. cDWI data in HT patients with and without ACR determined by gold standard EMB will be compared. Aim 2 is also sub-divided into technical (2A) and clinical (2B) goals: Aim 2A is focused on an advanced technical development of our cDWI sequence from Aim 1, modified for intravoxel incoherent motion (IVIM) with the goal of developing semi-quantitative perfusion imaging which can be performed without a contrast agent. Aim 2B will explore if cDWI IVIM perfusion imaging detects altered blood flow in HT patients with cardiac allograft vasculopathy (CAV). Perfusion fractions will be measured in patients with and without evidence of CAV determined by the gold standard ICA. The end-point of the clinical aims is to validate cDWI in the HT population and achieve a general proof of concept that myocardial characterization with cDWI is an achievable and accurate clinical tool. Our results may provide a threshold of altered diffusion/perfusion with cDWI and IVIM that will predict a positive EMB/ICA result - with safe deferral of costly and invasive tests in HT patients below this threshold. In Summary, this proposal aims at creating a new, clinically feasible cDWI sequence which addresses the unresolved issues of physiologic cardiac motion, which has until now prevented development and clinical use of cDWI for cardiac tissue characterization. Developing a robust cDWI sequence may change the existing management paradigm of HT patients by providing a completely non-invasive and risk-free method of allograft surveillance. Ultimately, we expect that the availability of routine cDWI will unlock the potentially game-changing role which cDWI may also have for non-invasive assessment, of myocardial injury abnormal myocardial perfusion in the future.